Download Sunvepra - Bristol-Myers Squibb Canada

PRODUCT MONOGRAPH
INCLUDING PATIENT MEDICATION INFORMATION
PrSUNVEPRA
*
asunaprevir
Capsule, 100 mg, Oral
Antiviral Agent
Bristol-Myers Squibb Canada
Montréal, Canada
Date of Preparation:
09 March 2016
Date of Revision :
January 26, 2017
*TM of Bristol-Myers Squibb Holdings Ireland used under license by Bristol-Myers Squibb
Canada.
Submission Control No: 199423
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Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3
SUMMARY PRODUCT INFORMATION ........................................................................3
INDICATIONS AND CLINICAL USE ..............................................................................3
CONTRAINDICATIONS ...................................................................................................3
WARNINGS AND PRECAUTIONS ..................................................................................4
ADVERSE REACTIONS....................................................................................................8
DRUG INTERACTIONS ..................................................................................................14
DOSAGE AND ADMINISTRATION ..............................................................................21
OVERDOSAGE ................................................................................................................23
ACTION AND CLINICAL PHARMACOLOGY ............................................................23
STORAGE AND STABILITY ..........................................................................................26
SPECIAL HANDLING INSTRUCTIONS .......................................................................26
DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................26
PART II: SCIENTIFIC INFORMATION ...............................................................................28
PHARMACEUTICAL INFORMATION..........................................................................28
CLINICAL TRIALS ..........................................................................................................28
MICROBIOLOGY ............................................................................................................35
NON-CLINICAL TOXICOLOGY ....................................................................................39
REFERENCES ..................................................................................................................41
PART III: PATIENT MEDICATION INFORMATION ........................................................42
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SUNVEPRA
asunaprevir
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Dosage Form / Strength
Administration
Oral
Capsule / 100 mg
Clinically Relevant Nonmedicinal
Ingredients
None
For a complete listing, see DOSAGE
FORMS, COMPOSITION AND
PACKAGING section.
INDICATIONS AND CLINICAL USE
SUNVEPRA (asunaprevir) is indicated in combination with other agents for the treatment of
chronic hepatitis C (CHC) in adult patients with hepatitis C virus (HCV) genotypes 1 or 4 and
compensated liver disease, including cirrhosis.
The following points should be considered when initiating treatment with SUNVEPRA:
•
Treatment with SUNVEPRA should be initiated and monitored by a physician
experienced in the treatment of CHC.
•
SUNVEPRA must not be administered as monotherapy (see WARNINGS AND
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
•
Treatment regimen is dependent on viral genotype and subtype (see DOSAGE AND
ADMINISTRATION).
•
SUNVEPRA has not been studied in patients who have previously failed therapy with a
treatment regimen that includes asunaprevir or other HCV protease inhibitors.
Geriatrics (≥ 65 years of age)
No overall differences in safety or effectiveness were observed in patients <65 and patients ≥65.
Pediatrics (< 18 years of age)
The safety and efficacy of SUNVEPRA have not been studied in pediatric patients.
CONTRAINDICATIONS
SUNVEPRA is contraindicated in patients who are hypersensitive to this drug or to any
ingredient in the formulation or component of the container. For a complete listing, see the
DOSAGE FORMS, COMPOSITION and PACKAGING section of the Product Monograph.
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When SUNVEPRA is used in combination with DAKLINZA, peginterferon alfa, and ribavirin,
the contraindications applicable to those agents are applicable to the combination regimen. Refer
to the respective Product Monographs for a list of contraindications.
The combination of SUNVEPRA with DAKLINZA, peginterferon alfa, and ribavirin is
contraindicated in women who are pregnant or may become pregnant and men whose female
partners are pregnant, may be pregnant or plan to become pregnant because of the risks of birth
defects and fetal death associated with ribavirin (see WARNINGS AND PRECAUTIONS;
Special populations, Pregnant Women, Use with Peginterferon Alfa and Ribavirin).
SUNVEPRA is contraindicated in patients with moderate or severe hepatic impairment (ChildPugh B or C, score 7 or greater) and patients with decompensated liver disease (see ACTION
AND CLINICAL PHARMACOLOGY).
SUNVEPRA is contraindicated in combination with drugs that are:
Dependent on the cytochrome P450 enzyme 2D6 (CYP2D6) for clearance and for which
elevated plasma concentrations are associated with serious venticular arrhythmias and
sudden death.
Moderate or strong inducers and inhibitors of CYP3A, which may lead to loss of
therapeutic effect or increased toxicity.
Strong inhibitors of organic anion transporting polypeptide (OATP) 1B1 or 2B1, which
may lead to loss of therapeutic effect.
See Table 4 (DRUG INTERACTIONS; Drugs Contraindicated with SUNVEPRA) for list of
drugs that are contraindicated.
WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
Hepatotoxicity: Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST)
elevations accompanied by increases in total bilirubin, with or
without pyrexia or
eosinophilia may occur (seeWARNINGS AND PRECAUTIONS, Hepatic, Potential for
Hepatotoxicity and ADVERSE REACTIONS; Potential for Hepatotoxicity)
Potential for Hepatitis B Virus (HBV) Reactivation: Screen all patients for evidence of
current or prior HBV infection before initiating SUNVEPRA treatment. Cases of HBV
reactivation, including those resulting in fulminant hepatitis, hepatic failure, and death, have
been reported during HCV treatment and/or post-treatment with regimens containing directacting antivirals (DAAs) in patients co-infected with HBV (see WARNINGS AND
PRECAUTIONS; Potential for Hepatitis B Virus Reactivation)
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General
SUNVEPRA must not
ADMINISTRATION).
be
administered
as
monotherapy
(see
DOSAGE
AND
Warnings and precautions for DAKLINZA, peginterferon alfa, and ribavirin also apply when
coadministered with SUNVEPRA.
Potential for Hepatitis B Virus Reactivation
Cases of HBV reactivation, including those resulting in fulminant hepatitis, hepatic failure, and
death have been reported in HCV/HBV coinfected patients who were undergoing, or completed
treatment with DAA. To decrease the risk of HBV reactivation in patients co-infected with
HBV, HBV screening should be performed in all patients prior to initiation of HCV treatment.
Patients with positive HBV serology (HBsAg positive) and patients with serologic evidence of
resolved HBV infection (i.e. HBsAg negative and anti-HBc positive) should be monitored and
treated according to current clinical practice guidelines to manage potential for HBV reactivation
(see WARNING AND PRECAUTIONS, Monitoring and Laboratory Tests).
Use in Patients with Other HCV Genotypes
The safety and efficacy of SUNVEPRA has not been studied in patients infected with HCV
genotypes 2, 3, 5 or 6.
Carcinogenesis and Mutagenesis
Asunaprevir was not carcinogenic in mice or in rats. No evidence of mutagenic or clastogenic
activity in vitro or in vivo assays (see NON-CLINICAL TOXICOLOGY).
Drug Interactions
The concomitant use of SUNVEPRA and other drugs may result in known or potentially
significant drug interactions (see DRUG INTERACTIONS; Drug-Drug Interactions). See
CONTRAINDICATIONS for drugs that are contraindicated for use with SUNVEPRA due to
potential for life-threatening adverse events, increased toxicity, or loss of therapeutic effect.
Hepatic
Potential for Hepatotoxicity
For patients receiving SUNVEPRA containing regimens, liver enzymes should be monitored at
least once every 2 weeks for the initial 12 weeks of treatment, and every 4 weeks thereafter until
completion of therapy. Any upward trend in alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) levels warrants more frequent monitoring. If on-treatment elevations in
ALT levels 10 times ULN or greater occur, treatment should be discontinued immediately and
not be resumed.
ALT and AST elevations were observed in phase 2 and 3 clinical trials of SUNVEPRA
containing regimens. Cases of potential drug-induced liver injury, defined as ALT/AST
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elevations accompanied by increases in total bilirubin, with or without pyrexia or eosinophilia,
occurred including a severe case in a patient with cirrhosis at week 6 of therapy in a clinical trial
of asunaprevir and daclatasvir combined with an investigational non-nucleoside HCV NS5B
inhibitor.
In clinical trials of SUNVEPRA combined with DAKLINZA or of SUNVEPRA combined with
DAKLINZA, peginterferon alfa, and ribavirin, the frequency of ALT and AST elevations at least
5 times upper limit of normal (ULN) was 3% to 4%, and the frequency of bilirubin elevations at
least 2.6 times ULN was 1% (see ADVERSE REACTIONS; Table 1). Frequencies of
ALT/AST elevations were higher in trials of SUNVEPRA plus DAKLINZA conducted in Japan
than in global trials of this regimen. In HALLMARK NIPPON, conducted in Japan, 7% of
patients had ALT greater than 5 times ULN while 2% of patients in the global study
HALLMARK DUAL had ALT greater than 5 times ULN. In SUNVEPRA and DAKLINZA
trials, ALT/AST elevations had a medium time to onset of 13 weeks after initiation of therapy
(range: 4-24 weeks) and in most cases returned to normal limits despite continued therapy.
These liver enzyme elevations were also reversible in subjects who discontinued therapy.
Hepatic Impairment
SUNVEPRA is contraindicated for patients with moderate or severe hepatic impairment since an
appropriate dose has not been established (see CONTRAINDICATIONS).
In a pharmacokinetic study in non–HCV-infected subjects with mild (Child-Pugh A), moderate
(Child-Pugh B), and severe (Child-Pugh C) hepatic impairment, asunaprevir steady-state
exposures were markedly higher in subjects with moderate or severe hepatic impairment (see
ACTION AND CLINICAL PHARMACOLOGY).
Patients with mild hepatic impairment (Child-Pugh A) who are administered SUNVEPRA
should be monitored closely with appropriate clinical evaluation during therapy to ensure that no
worsening of hepatic function is occurring that would necessitate discontinuation of therapy.
Cirrhosis
SUNVEPRA is contraindicated for patients with decompensated cirrhosis. Of more than 1300
patients in five clinical studies of SUNVEPRA combination therapy, 322 patients had
compensated cirrhosis (Child-Pugh A). No overall differences in safety or effectiveness were
observed between patients with compensated cirrhosis and subjects without cirrhosis.
Renal
For patients with severe renal impairment [creatinine clearance (CrCl) less than 30 mL/min] who
are not receiving hemodialysis, the recommended dose of SUNVEPRA is 100 mg once daily.
No dosage adjustment of SUNVEPRA is required for the majority of renally impaired patients
including those receiving hemodialysis or those with mild or moderate renal impairment (CrCl
30 mL/min or greater) (see ACTION AND CLINICAL PHARMACOLOGY).
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Sexual Function/Reproduction
There are no data on the effect of asunaprevir on human fertility. No effects on fertility were
observed in animal studies (see NON-CLINICAL TOXICOLOGY).
Special Populations
Pregnant Women
SUNVEPRA has not been studied in pregnant women. For a summary of findings from
reproductive toxicity studies in animals, see NON-CLINICAL TOXICOLOGY.
SUNVEPRA in combination with DAKLINZA should not be used during pregnancy or in
women of childbearing potential not using contraception (refer to the Product Monograph for
DAKLINZA). For patients using oral contraception, a high-dose oral contraceptive (containing
at least 30 µg of ethinyl estradiol combined with norethindrone acetate/norethindrone) is
recommended (see DRUG INTERACTIONS).
Use with Peginterferon Alfa and Ribavirin
Ribavirin may cause birth defects and/or death of the exposed fetus, and animal studies have
shown that interferons have abortifacient effects (see CONTRAINDICATIONS). Extreme care
must be taken to avoid pregnancy in female patients and in female partners of male patients.
Ribavirin therapy should not be started unless a report of a negative pregnancy test has been
obtained immediately before initiation of therapy.
When SUNVEPRA is used in combination with DAKLINZA, peginterferon alfa, and ribavirin,
women of childbearing potential and their male partners must use 2 forms of effective
contraception during treatment and for at least 6 months after treatment has concluded. Routine
monthly pregnancy tests must be performed during this time. If oral contraception is one of the
forms of contraception, a high-dose oral contraceptive (containing at least 30 µg of ethinyl
estradiol combined with norethindrone acetate/norethindrone) is recommended. Refer also to the
Product Monograph for peginterferon alfa and ribavirin.
Nursing Women
Mothers should be instructed not to breastfeed if they are taking SUNVEPRA. It is not known
whether asunaprevir is present in human milk. Pharmacokinetic data in animals have shown the
presence of asunaprevir and its metabolites in milk.
Pediatrics (˂18 years of age)
The safety and efficacy of SUNVEPRA have not been studied in pediatric patients younger than
18 years of age.
Geriatrics (≥ 65 years of age)
Of more than 1300 patients in five clinical studies of SUNVEPRA combination therapy, 275
were 65 years and older and 20 were 75 and older. No overall differences in safety or
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effectiveness were observed between these patients and younger subjects.
Liver Transplant Patients
The safety and efficacy of SUNVEPRA combination therapy have not been studied in liver
transplant patients.
HCV/HIV-1 Co-infection
The safety and efficacy of SUNVEPRA have not been studied in HCV patients co-infected with
HIV-1 (Human Immunodeficiency Virus).
HCV/HBV Co-infection
The safety and efficacy of SUNVEPRA have not been studied in HCV patients co-infected with
HBV (Hepatitis B Virus).
HBV reactivation has been reported during treatment and post-treatment with DAA regimens in
patients co-infected with HBV who were not undergoing treatment for HBV infection (see
WARNINGS AND PRECAUTIONS; Potential for Hepatitis B Virus Reactivation).
Monitoring and Laboratory Tests
Liver enzymes should be monitored at least once every 2 weeks for the initial 12 weeks of
treatment, and every 4 weeks thereafter until completion of therapy. Any upward trend in ALT
or AST levels warrants more frequent monitoring. If on-treatment elevations in ALT levels
10 times ULN or greater occur, treatment should be discontinued immediately and not be
resumed (see WARNINGS AND PRECAUTIONS; Hepatic, Potential for Hepatic Toxicity).
Clearance of HCV may lead to increased replication of HBV in patients who are HCV/HBV coinfected. Co-infected patients who show evidence of current or prior HBV infection should
undergo periodic monitoring for clinical and laboratory signs (e.g. HBsAg, HBV DNA, serum
aminotransferase levels, bilirubin) for HBV reactivation during and at post-treatment follow-up.
Consult a physician with expertise in the management of HBV regarding the consideration for
HBV antiviral therapy in HCV/HBV co-infected patients (see WARNINGS AND
PRECAUTIONS; Potential for Hepatitis B Virus Reactivation).
ADVERSE REACTIONS
Adverse Drug Reaction Overview
SUNVEPRA must be administered with other medicinal products for the treatment of chronic
HCV infection. Refer to the full Product Monograph for DAKLINZA, peginterferon alfa, and
ribavirin for their associated adverse reactions.
The potential for hepatotoxicity is discussed in greater detail in the WARNINGS AND
PRECAUTIONS; Hepatic, Potential for Hepatotoxicity section.
The safety assessment of SUNVEPRA is based on data from 1316 patients with chronic HCV
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infection who received SUNVEPRA with DAKLINZA (n=918) or with DAKLINZA,
peginterferon alfa, and ribavirin (n=398) for 24 weeks in five clinical trials. Of the 1316 subjects,
1265 (96%) received 100 mg twice daily of the marketed 100 mg soft gelatin capsule
formulation of asunaprevir, and 51 (4%) received 200 mg twice daily of a 200 mg dry granulated
tablet. The 100 mg marketed capsule formulation has exposures comparable to the 200 mg tablet
(administered with food) (see CLINICAL TRIALS; Table 11 for demographic information).
The safety experience in these trials is presented by regimen.
SUNVEPRA in Combination with DAKLINZA
The safety of SUNVEPRA in combination with DAKLINZA was assessed in 918 patients with
chronic HCV infection in four open-label clinical trials (HALLMARK DUAL [AI447028],
HALLMARK NIPPON [AI447026], AI447017, AI447011).
The most common adverse reactions (any severity, frequency of 10% or greater) were headache
(15%) and fatigue (12%). Most adverse reactions were mild to moderate in severity. Six percent
(56/918) of patients experienced a serious adverse event (SAE). SAEs considered treatmentrelated and reported in more than one patient were pyrexia and ALT increased. Three percent
(23/918) of patients discontinued for adverse events; the most common adverse events leading to
discontinuation (1% or greater) were increase in ALT (15/918; 2%) and increase in AST
(12/918; 1%). Overall, 2% (19/918) of patients discontinued study therapy due to at least
1 adverse event that involved elevations of liver function tests (ALT increased, AST increased,
blood bilirubin increased, transaminases increased, or hypertransaminasemia) (see WARNINGS
AND PRECAUTIONS; Hepatic, Potential for Hepatotoxicity).
In the HALLMARK DUAL study during the first 12 weeks of treatment, rates of adverse
reactions reported were similar between treatment-naive patients treated with placebo and
patients treated with SUNVEPRA in combination with DAKLINZA.
SUNVEPRA in Combination with DAKLINZA Plus Peginterferon alfa and Ribavirin
The safety of SUNVEPRA in combination with DAKLINZA, peginterferon alfa, and ribavirin
was assessed in 398 patients with chronic HCV genotype 1 or 4 infection in an open-label
clinical trial (HALLMARK QUAD [AI447029]). The most common adverse reactions (any
severity, frequency of 15% or greater) were fatigue (39%), headache (28%), pruritus (25%),
asthenia (23%), influenza-like illness (22%), insomnia (21%), anemia (19%), rash (18%),
alopecia (16%), irritability (16%), and nausea (15%). Most adverse reactions were mild to
moderate in severity. Six percent (22/398) of patients experienced an SAE. The only SAE
considered treatment-related and reported in more than 1 patient was anemia. Five percent
(18/398) of patients discontinued for adverse events. Rash, malaise, vertigo, and neutropenia
were the most common adverse events leading to discontinuation of study therapy (each reported
in 2 (0.5%) patients).
Asthenia and influenza-like illness were the only adverse reactions that occurred with a
frequency at least 5% greater in HALLMARK QUAD than in patients treated with placebo,
peginterferon alfa, and ribavirin from six phase 2 placebo-controlled clinical trials (n=174).
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Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice. Adverse drug reaction
information from clinical trials is useful for identifying drug-related adverse events and for
approximating rates.
Adverse reactions of at least moderate severity (Grades 2-4) and considered at least possibly
related to treatment and occurring at a frequency of 3% or greater in clinical trials of
SUNVEPRA in combination with DAKLINZA are presented in Table 1.
Table 1:
Adverse Reactions of at Least Moderate Severity Reported in ≥3% of
Patients in Clinical Trials of SUNVEPRA in Combination with
DAKLINZA (DUAL)
Percent with Adverse Reactiona
n=918
Adverse Reaction
Hepatobiliary Disorder
Increase in ALT
Increase in AST
a
24 weeks
5%
3%
Events of at least moderate severity (Grades 2-4) with at least a possible relationship to study drug (investigator
attribution) and occurring in at least 3% of patients. Integrated data from four open-label phase 2/3 studies
(HALLMARK DUAL, HALLMARK NIPPON, AI447017, and AI447011) in patients infected with HCV
genotype 1b.
Adverse reactions of at least moderate severity (Grades 2-4) and considered at least possibly
related to treatment and occurring at a frequency of 3% or greater in HALLMARK QUAD
(SUNVEPRA in combination with DAKLINZA, peginterferon alfa, and ribavirin) are presented
in Table 2.
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Table 2:
Adverse Reactions of at Least Moderate Severity Reported in ≥3% of
Patients in HALLMARK QUAD, SUNVEPRA in Combination with
DAKLINZA, Peginterferon Alfa, and Ribavirin (QUAD)
Percent with Adverse Reactionsa
QUADb
Adverse Reaction
24 weeks
n=398
Blood and Lymphatic Disorders
Neutropenia
11%
Anemia
11%
Thrombocytopenia
5%
Gastrointestinal Disorders
Nausea
4%
General Disorders nd Administration Site
Conditions
Fatigue
11%
Asthenia
7%
Influenza-like illness
4%
Investigations
Weight decreased
3%
Nervous System Disorders
Headache
6%
Psychiatric Disorders
Insomnia
4%
Depression
4%
Skin and Subcutaneous Tissue Disorders
Pruritus
6%
Rash
5%
Alopecia
3%
Dry skin
3%
a
Events of at least moderate severity (Grades 2-4) with at least a possible relationship to study drug (investigator
attribution) and occurring in at least 3% of patients in HALLMARK QUAD.
b
HALLMARK QUAD, a phase 3 study that included patients infected with HCV genotype 1 or 4.
Less Common Clinical Trial Adverse Drug Reactions
SUNVEPRA in combination with DAKLINZA (integrated data from studies HALLMARK
DUAL, HALLMARK NIPPON, AI447017, and AI447011).
Additional adverse reactions of at least moderate severity (Grades 2-4) reported in clinical
studies of SUNVEPRA administered in combination with other oral agents for the treatment of
HCV infection at a frequency of <3% are listed below by body system.
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Blood and Lymphatic System Disorders: eosinophilia, lymphopenia, thrombocytopenia.
Cardiac Disorders: atrial fibrillation.
Gastrointestinal Disorders: abdominal pain, constipation, diarrhea, dyspepsia, nausea.
General Disorders and Administration Site Conditions: asthenia, fatigue, malaise, pyrexia.
Infections and infestations: influenza, nasopharyngitis.
Investigations: increased blood bilirubin.
Metabolism and Nutrition Disorders: decreased appetite.
Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia.
Nervous System Disorders: amnesia, disturbance in attention, dizziness, headache.
Psychiatric Disorders: insomnia.
Respiratory, Thoracic, and Mediastinal Disorders: cough, dyspnea, oropharyngeal pain.
Skin and Subcutaneous Tissue Disorders: alopecia, pruritus, psoriasis, rash.
Vascular Disorders: hypertension.
SUNVEPRA in Combination with DAKLINZA, Peginterferon Alfa, and Ribavirin (Study
HALLMARK QUAD)
Additional adverse reactions of at least moderate severity (Grades 2-4) reported in HALLMARK
QUAD at a frequency of <3% are listed below by body system.
Blood and Lymphatic System Disorders: leukopenia, lymphopenia.
Eye Disorders: dry eye.
Ear and Labyrinth Disorders: vertigo.
Gastrointestinal Disorders: abdominal pain, constipation, diarrhea, dyspepsia, dysphagia,
hemorrhoids, stomatitis, vomiting.
General Disorders and Administration Site Conditions: irritability, malaise, pain, pyrexia.
Hepatobiliary Disorders: hyperbilirubinemia.
Investigations: weight decreased.
Metabolism and Nutrition Disorders: decreased appetite.
Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain, musculoskeletal chest
pain, myalgia.
Nervous System Disorders: disturbance in attention, dizziness, syncope.
Psychiatric Disorders: anxiety, mood swings, sleep disorder.
Respiratory, Thoracic, and Mediastinal Disorders: cough, dyspnea, dyspnea exertional.
Skin and Subcutaneous Tissue Disorders: dermatitis, dermatitis exfoliative, eczema, erythema,
generalized rash, maculopapular rash, seborrheic.
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Abnormal Clinical Chemistry Findings
Grades 2-4 liver enzyme and bilirubin elevations observed in HCV-infected subjects treated with
SUNVEPRA combination therapy are presented in Table 3 (see WARNINGS AND
PRECAUTIONS). Laboratory data from the placebo, peginterferon alfa, and ribavirin arms of
six phase 2 placebo-controlled clinical trials are included in Table 3.
Table 3:
Grades 2-4 Liver Enzyme and Bilirubin Elevations in Clinical Trials
of SUNVEPRA in Combination with DAKLINZA, with or without
Peginterferon Alfa and Ribavirin
Percent with Abnormality
Interferon-containing Regimens
Parameter
a
DUAL
b
n=918
QUAD
c
n=398
Placebo with
Peginterferon Alfa
and Ribavirin
n=174
ALT increased (≥2.6× ULN)
12%
11%
13%
AST increased (≥2.6× ULN)
9%
13%
10%
Total bilirubin increased
(≥1.6 × ULN)
4%
10%
8%
a
d
Laboratory results were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and
Pediatric Adverse Events, Version 1.0.
b
Integrated data from four open-label phase 2/3 studies (HALLMARK DUAL, HALLMARK NIPPON,
AI447017, and AI447011) in patients infected with HCV genotype 1b.
c
Data from HALLMARK QUAD, a phase 3 study of SUNVEPRA, DAKLINZA, peginterferon alfa, and ribavirin
in patients infected with HCV genotype 1 or 4.
d
Data from subjects who received placebo, peginterferon alfa, and ribavirin in six phase 2 clinical trials.
Potential for Hepatotoxicity
ALT and AST elevations were observed in phase 2 and 3 clinical trials of SUNVEPRAcontaining regimens (see Table 3). Cases of potential drug-induced liver injury, defined as
ALT/AST elevations accompanied by increases in total bilirubin, with or without pyrexia or
eosinophilia, occurred including a severe case in a patient with cirrhosis at week 6 of therapy in a
clinical trial of asunaprevir and daclatasvir combined with an investigational non-nucleoside
HCV NS5B inhibitor (see WARNINGS AND PRECAUTIONS, Hepatic, Potential for
Hepatotoxicity).
Post-Market Adverse Drug Reactions
Because postmarketing adverse reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
The following additional adverse reaction was identified during post approval use of
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SUNVEPRA:
Skin and Subcutaneous Tissue Disorders:
erythema multiforme
DRUG INTERACTIONS
Serious Drug Interactions
Co-administration of drugs that are moderate or strong inducers of CYP3A (e.g. rifampin) may
lead to loss of therapeutic effect of SUNVEPRA.
Co-administration of drugs that are moderate or strong inhibitors of CYP3A (e.g. ketoconazole)
may lead to an increase in the likelihood and severity of liver related events.
Co-administration of strong inhibitors of organic anion transporting polypeptide (OATP) 1B1
or 2B1 (e.g. cyclosporine) may lead to loss of therapeutic effect of SUNVEPRA.
Asunaprevir is a moderate inhibitor of CYP2D6. Co-administration of drugs that are sensitive
substrates of CYP2D6 with a narrow therapeutic index (e.g. thioridazine) may lead to an
increase in adverse events (See CONTRAINDICATIONS and DRUG INTERACTIONS;
Established and Other Potentially Significant Drug Interactions, Table 5).
Refer to the respective Product Monographs of other drugs in the regimen for drug interaction
information. The most conservative recommendation should be followed.
Overview
See Table 5 for steps to prevent or manage other possible and known significant drug
interactions. Consider the potential for drug interactions before and during SUNVEPRA therapy,
review concomitant medications during SUNVEPRA therapy, and monitor for the adverse
reactions associated with the concomitant drugs.
Drug-Drug Interactions
Potential for Other Drugs to Affect SUNVEPRA
CYP3A is involved in the elimination of asunaprevir. Therefore, moderate or strong inducers
of CYP3A may decrease the plasma levels of asunaprevir, and moderate or strong inhibitors of
CYP3A may increase the plasma levels of asunaprevir (see CONTRAINDICATIONS).
Asunaprevir is also a substrate of P-glycoprotein transporter (P-gp), but coadministration of
agents that modify P-gp activity alone (without concurrent effect on CYP3A) is unlikely to have
a clinically meaningful effect on asunaprevir exposure. OATP 1B1 and 2B1 are involved in the
liver distribution of asunaprevir. Therefore, strong inhibitors of OATP-mediated transport may
increase the plasma concentrations of asunaprevir and decrease its therapeutic effect by reducing
distribution to the liver (see CONTRAINDICATIONS).
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Potential for SUNVEPRA to Affect Other Drugs
Asunaprevir is a moderate inhibitor of CYP2D6 (see CONTRAINDICATIONS), a weak
inhibitor of OATP 1B1/1B3/2B1- and P-gp–mediated transport, and a weak inducer of CYP3A.
Caution should be used when SUNVEPRA is administered with substrates of these enzymes or
transporters, with close clinical monitoring for both desired therapeutic outcomes and adverse
reactions. Asunaprevir, in vitro, did not inhibit (IC50 >40 µM) CYP1A2, CYP2C9, or
CYP2C19. In vitro asunaprevir is a weak inhibitor of renal uptake transporters, organic anion
transporter (OAT) 1 and 3, and organic cation transporter (OCT) 1 and 2, but is not expected to
have a clinical effect on the pharmacokinetics of substrates of these transporters.
Drugs Contraindicated with SUNVEPRA
Contraindicated drugs include, but are not limited to, those listed in Table 4 (see
CONTRAINDICATIONS).
Table 4:
Drugs that are Contraindicated with SUNVEPRA
Drugs that Are Contraindicated
with SUNVEPRA
a
Antipsychotic agent
thioridazine
Mechanism of Interaction
Clinical Comment
Inhibition of CYP2D6 by
asunaprevir
Increased concentrations may result
in cardiac arrhythmias or sudden
death
Strong or moderate induction of
CYP3A by coadministered drug
May lead to loss of therapeutic
effect of SUNVEPRA.
Strong or moderate inhibition of
CYP3A by coadministered drug
Increased concentrations of
SUNVEPRA may increase the
likelihood and severity of liverrelated adverse events.
Anticonvulsants
carbamazepine, oxcarbazepine,
phenobarbital, phenytoin
Anti-infective agents
b
nafcillin , rifabutin, rifampin,
rifapentine
b
Endothelin receptor antagonist
bosentan
Glucocorticoid, systemic
dexamethasone
Herbal products
St. John’s wort (Hypericum
perforatum)
HIV non-nucleoside reverse
transcriptase inhibitors
efavirenz, etravirine, nevirapine
Wakefulness-promoting agent
modafinil
Antifungal agents
fluconazole, itraconazole,
ketoconazole, posaconazole,
voriconazole
Anti-infective agents
clarithromycin, erythromycin,
b
telithromycin
Calcium channel blocker
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Table 4:
Drugs that are Contraindicated with SUNVEPRA
Drugs that Are Contraindicated
with SUNVEPRA
a
Mechanism of Interaction
Clinical Comment
diltiazem, verapamil
HIV protease inhibitors
atazanavir, darunavir/ritonavir,
fosamprenavir, indinavir,
lopinavir/ritonavir, nelfinavir,
ritonavir, saquinavir
Pharmacokinetic enhancer
cobicistat or cobicistat-containing
regimen
Antiarrhythmics
Flecainide
Propafenone
Antimycobacterial agent
rifampin
Immunosuppressants
cyclosporine
Lipid-lowering agent
gemfibrozil
a
Sensitive substrates of CYP2D6
with a narrow therapeutic range
Increased concentrations of
flecainide and propafenone may
result in adverse events.
Strong inhibition of OATP 1B1 or
2B1
May lead to loss of therapeutic
effect of SUNVEPRA.
This table is not a comprehensive list of strong and moderate inducers or inhibitors of CYP3A or strong
inhibitors of OATP 1B1 or 2B1.
b
Not marketed in Canada.
Established and Potentially Significant Drug Interactions
Clinical recommendations for established or potentially significant drug interactions between
SUNVEPRA and other drugs are summarized in Table 5.
Table 5:
Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Namea
Effect on
Concentrationb
Clinical Comment
Anticoagulants
Dabigatran etexilate
↑ Dabigatran etexilate
Close clinical monitoring is recommended when
initiating therapy with SUNVEPRA in patients
receiving dabigatran etexilate or other intestinal Pgp substrates that have a narrow therapeutic range.
Antidepresssants
Tricyclics
Amitriptyline
Imipramine
Nortriptyline
SUNVEPRA (asunaprevir)
↑ Amitriptyline
↑ Imipramine
↑ Nortriptyline
Close clinical monitoring is recommended when
sensitive substrates of CYP2D6 with a narrow
therapeutic range, including certain tricyclic
antidepressants (TCA), are administered with
SUNVEPRA. Plasma concentrations of the TCA
may need to be monitored and the dose of the TCA
reduced [see DRUG INTERACTIONS, DrugDrug Interactions, Potential for SUNVEPRA to
Affect Other Drugs].
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Table 5:
Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Namea
Effect on
Concentrationb
Clinical Comment
↑ Dextromethorphan
Close clinical monitoring is recommended when
dextromethorphan or other sensitive substrates of
CYP2D6 are administered with SUNVEPRA. Dose
reduction of sensitive CYP2D6 substrates should be
considered [see DRUG INTERACTIONS, DrugDrug Interactions, Potential for SUNVEPRA to
Affect Other Drugs].
↑ Digoxin
Digoxin and other P-gp substrates with a narrow
therapeutic range should be used with caution when
administered with SUNVEPRA. The lowest dose of
digoxin should be initially prescribed. The serum
digoxin concentrations should be monitored and
used for titration of digoxin dose to obtain the
desired clinical effect.
Antitussives
Dextromethorphan
c
Cardiovascular agents
Antiarrhythmic:
c
Digoxin
Hormonal contraceptives
Ethinyl estradiol +
c
norgestimate
Ethinyl estradiol +
norethindrone
acetate/norethindronec
↓ Ethinyl estradiol
↓ Norelgestromin
For patients using oral contraception, a high-dose
oral contraceptive (containing at least 30 µg of
ethinyl estradiol combined with norethindrone
acetate/norethindrone) is recommended during
treatment with SUNVEPRA.
Lipid-lowering agents
HMG-CoA reductase inhibitor:
Atorvastatin
Fluvastatin
Pravastatin
Rosuvastatin
Simvastatin
↑ Rosuvastatin
Treatment with rosuvastatin and other
OATP 1B1/1B3 substrates can be initiated at the
recommended dose when coadministered with
SUNVEPRA. Close clinical monitoring for both
desired therapeutic outcomes and side effects of the
OATP substrate is recommended.
↓ Midazolam
Coadministration of SUNVEPRA with midazolam
and other medicinal products that are highly
dependent on CYP3A for elimination and for which
reduced plasma concentrations may be associated
with reduced therapeutic effect should be
approached with caution. These other medicinal
products include but are not limited to alfentanil,
fentanyl, quinidine and triazolam.
c
Sedatives
Benzodiazepine:
c
Midazolam
a
This table is not all inclusive.
b
The direction of the arrow (↑ = increase, ↓ = decrease) indicates the direction of the change in pharmacokinetic
parameters.
c
These interactions have been studied (see Tables 6, 7 below).
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Assessment of Drug Interactions
Drug interaction studies were conducted with asunaprevir and other drugs likely to be
coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects
of asunaprevir on the Cmax, AUC, and Cmin of the coadministered drug are summarized in Table 6
and the effects of the coadministered drug on the Cmax, AUC, and Cmin of asunaprevir are
summarized in Table 7. Drug interaction studies were conducted in healthy adults unless
otherwise noted.
Table 6:
Effect of SUNVEPRA on the Pharmacokinetics of Concomitant Drugs
Concomitant
Drug
Caffeine
Daclatasvir
Coadministered
Drug Dose
SUNVEPRA
Dose
N
a
19
b
26
200 mg single
dose
200 mg BID
30 mg QD
200 mg BID
Ratio (90% CI) of Pharmacokinetic Parameters
of Coadministered Drugs With/Without
Asunaprevir
No Effect=1.00
Cmax
AUC
Cmin
0.95
(0.91, 1.00)
0.96
(0.89, 1.04)
NA
1.07
(0.97, 1.18)
c
1.20
(1.11, 1.30)
c
1.33
(1.22, 1.45)
Dextromethorphan
30 mg single
dose
200 mg BID
a
17
2.72
(2.10, 3.53)
3.94
(3.09, 5.03)
NA
Digoxin
0.5 mg single
dose
200 mg BID
a
16
1.09
(0.97, 1.22)
1.30
(1.21, 1.40)
NA
0.25 mg single
dose
100 mg BID
and
daclatasvir
60 mg QD
16
1.77
(1.50, 2.07)
1.29
(1.20, 1.39)
NA
10 mg QD
100 mg BID
16
0.97
(0.92, 1.02)
0.95
(0.91, 0.98)
NA
Ethinyl estradiol/
norgestimate
35 µg QD/
0.180/0.215/
0.250 mg QD
600 mg BID
a
17
Ethinyl
estradiol:
0.75
(0.67, 0.85)
Norelgestromin:
0.71
(0.65, 0.77)
Ethinyl
estradiol:
0.72
(0.67, 0.78)
Norelgestromin:
0.66
(0.62, 0.70)
NA
Ethinyl estradiol/
norethindrone
acetate
30 µg QD/
1.5 mg QD
(high-dose oral
contraceptive)
100 mg BID
and
daclatasvir
60 mg QD
36
Ethinyl
estradiol:
0.93
(0.86, 0.99)
Norethindrone:
0.93
(0.85, 1.01)
Ethinyl
estradiol:
0.86
(0.83, 0.89)
Norethindrone:
1.02
(0.94, 1.11)
NA
36
Ethinyl
Ethinyl
NA
estradiol :
estradiol :
Escitalopram
SUNVEPRA (asunaprevir)
d
d
c
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Table 6:
Concomitant
Drug
Effect of SUNVEPRA on the Pharmacokinetics of Concomitant Drugs
Coadministered
Drug Dose
SUNVEPRA
Dose
N
Ratio (90% CI) of Pharmacokinetic Parameters
of Coadministered Drugs With/Without
Asunaprevir
No Effect=1.00
Cmax
AUC
1.36
(1.28, 1.45)
1.27
(1.21, 1.33)
d
Cmin
d
Norethindrone :
1.26
(1.17, 1.36)
Norethindrone :
1.43
(1.34, 1.52)
Losartan
25 mg single
dose
200 mg BID
a
18
1.63
(1.35, 1.97)
0.89
(0.81, 0.98)
NA
Methadone
stable
maintenance
40-120 mg
100 mg BID
15
Total
methadone:
1.00
(0.89, 1.12)
R-methadone:
0.97
(0.86, 1.08)
Total
methadone:
0.94
(0.84, 1.05)
R-methadone:
0.91
(0.82, 1.01)
Total
methadone:
0.91
(0.80, 1.03)
Rmethadone:
0.88
(0.80, 0.98)
Midazolam
5 mg single oral
dose
200 mg BID
a
19
0.79
(0.73, 0.87)
0. 71
(0.67, 0.75)
NA
Omeprazole
40 mg single
dose
200 mg BID
a
18
0.96
(0.79, 1.16)
0.80
(0.69, 0.94)
NA
Peginterferon
180 µg once
weekly
200 mg BID
a
10
↔
f
↔
f
↔
1000 or 1200
mg/day in two
divided doses
200 mg BID
a
11
↔
f
↔
f
↔
10 mg single
dose
200 mg BID
a
20
1.95
(1.47, 2.58)
1.41
(1.26, 1.57)
NA
50 mg QD
100 mg BID
18
0.81
(0.67, 0.97)
0.79
(0.67, 0.94)
NA
alfa
e
e
Ribavirin
Rosuvastatin
Sertraline
a
f
f
Asunaprevir tablet (not marketed) 200 mg administered with food has similar bioavailability as asunaprevir soft
capsule 100 mg.
b
Nonmarketed capsule formulation.
c
Results are dose-normalized to 60 mg dose of daclatasvir.
d
Pharmacokinetics of ethinyl estradiol/norethindrone when high-dose oral contraceptive is administered with
asunaprevir and daclatasvir compared with pharmacokinetics of ethinyl estradiol/norethindrone when a low-dose
oral contraceptive (ethinyl estradiol 20 µg QD/norethindrone 1 mg QD) is administered alone.
e
Study conducted in subjects with chronic HCV infection.
f
Pharmacokinetic parameters for peginterferon alfa and ribavirin in subjects who received peginterferon alfa,
ribavirin, and asunaprevir were similar to those in subjects who received peginterferon alfa, ribavirin, and
placebo.
SUNVEPRA (asunaprevir)
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NA = Not available.
Table 7:
Concomitant
Drug
Effect of Coadministered Drugs on the Pharmacokinetics of SUNVEPRA
Coadministered
Drug Dose
SUNVEPRA
Dose
N
Ratio (90% CI) of Pharmacokinetic Parameters
of Asunaprevir With/Without Coadministered
Drugs
No Effect=1.00
AUC
Cmax
Daclatasvir
30 mg QD
200 mg BID
a
26
0.58
0.87
Cmin
b
1.76
b
(0.45, 0.76)
(0.73, 1.04)
(1.42, 2.17)
b
Escitalopram
10 mg QD
100 mg BID
16
0.87
(0.65, 1.18)
0.92
(0.76, 1.12)
NA
Ketoconazole
200 mg BID
200 mg BID
c
19
6.92
(5.92, 8.09)
9.65
(8.64, 10.77)
9.35
(8.31, 10.53)
Peginterferon
180 µg once
weekly
200 mg BID
c
11
↔
Ribavirin
1000 or 1200
mg/day in two
divided doses
200 mg BID
c
11
Rifampin
600 mg single
dose
200 mg single
600 mg QD
600 mg BID
50 mg QD
alfa
d
d
Sertraline
a
e
↔
e
↔
e
↔
e
↔
e
↔
e
20
21.11
(14.27, 31.24)
14.81
(11.22, 19.53)
NA
c
20
0.95
(0.60, 1.50)
0.79
(0.56, 1.09)
NA
100 mg BID
18
0.94
(0.70, 1.28)
0.88
(0.70, 1.11)
NA
dose fasted
c
Nonmarketed capsule formulation.
b
Results are dose-normalized to 600 mg dose.
c
Asunaprevir tablet (not marketed) 200 mg administered with food has similar bioavailability as asunaprevir soft
capsule 100 mg.
d
Study conducted in subjects with chronic HCV infection.
e
Pharmacokinetic parameters for asunaprevir when administered with peginterferon and ribavirin in this study
were similar to those observed in a study of HCV-infected subjects administered asunaprevir and daclatasvir for
14 days.
NA = Not available.
Drugs without Significant Interactions with SUNVEPRA
Based on the results of drug interaction studies (see Tables 6, 7 above), no clinically significant
drug interactions were observed when SUNVEPRA was used with the following drugs:
daclatasvir, escitalopram, methadone, peginterferon alfa, ribavirin, sertraline, caffeine and other
CYP1A2 substrates, losartan and other CYP2C9 substrates, or omeprazole and other CYP2C19
substrates.
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Drug-Food Interactions
No drug-food interaction was observed. SUNVEPRA can be taken without regard to food.
Drug-Herb Interactions
St. John’s wort is contraindicated with SUNVEPRA since coadministration of St. John’s wort, an
inducer of CYP3A, may decrease SUNVEPRA plasma concentrations (see
CONTRAINDICATIONS).
Drug-Laboratory Interactions
Interactions of SUNVEPRA with laboratory tests have not been established.
DOSAGE AND ADMINISTRATION
Dosing Considerations
SUNVEPRA must not be administered as monotherapy.
Treatment regimen is dependent on viral genotype.
SUNVEPRA can be taken without regard to food.
Testing Prior to the Initiation of Therapy
Screen all patients for evidence of current or prior HBV infection by measuring HBsAg and antiHBc before initiating treatment for HCV with SUNVEPRA (see WARNING AND
PRECAUTIONS, Monitoring and Laboratory Test).
Recommended Dose
The recommended dose of SUNVEPRA for adults is 100 mg, taken orally, twice daily for 24
weeks.
The recommended treatment regimens with SUNVEPRA, based on viral genotype, are provided
in Table 8. For specific dose recommendations for other agents in the regimen, refer to the
respective Product Monographs.
Table 8:
Treatment Regimens and Duration by Patient Population
Patient Population
Genotype 1b
a
Treatment
Duration of
Treatment
SUNVEPRA and DAKLINZA (DUAL)
24 weeks
SUNVEPRA, DAKLINZA,
peginterferon alfa, and ribavirin (QUAD)
24 weeks
Treatment-naive or treatmentb
experienced , with or without
compensated cirrhosis
Genotype 1 or 4
Treatment-naive
a,c
or treatment-
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Table 8:
Treatment Regimens and Duration by Patient Population
Patient Population
Treatment
Duration of
Treatment
b
experienced , with or without
compensated cirrhosis
a
Treatment naive is defined as no prior exposure to any interferon, ribavirin, or other approved or experimental
HCV-specific direct-acting antiviral agent at the time of treatment initiation.
b
Treatment-experienced is defined as those who failed prior therapy with an interferon-based regimen, including
null or partial response, or intolerant to or ineligible for interferon-based therapy (see CLINICAL TRIALS;
Tables 11, 14 for more detailed definitions).
c
Clinical trial experience with the QUAD regimen in treatment-experienced patients is extrapolated to treatmentnaive patients.
Special Populations
Pediatrics (<18 years of age)
SUNVEPRA has not been studied in pediatric patients <18 years of age.
Geriatrics (≥65 years of age)
No dose adjustment of SUNVEPRA is required for elderly patients.
Renal Impairment
For patients with severe renal impairment [creatinine clearance (CrCl) less than 30 mL/min] who
are not receiving hemodialysis, the recommended dose of SUNVEPRA is 100 mg once daily.
No dosage adjustment of SUNVEPRA is required for the majority of renally impaired patients
including those receiving hemodialysis or those with mild or moderate renal impairment (CrCl
30 mL/min or greater) (see ACTION AND CLINICAL PHARMACOLOGY; Special
Populations and Conditions; Renal Impairment).
Hepatic Impairment
SUNVEPRA is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh
C) hepatic impairment (see CONTRAINDICATIONS).
No dose adjustment of SUNVEPRA is required for patients with mild hepatic impairment
(Child-Pugh A) (see WARNINGS AND PRECAUTIONS).
Dose Modification and Interruption
Dose modification of SUNVEPRA or DAKLINZA for adverse reactions is not recommended.
Refer to the respective Product Monograph for dose modification of peginterferon alfa and
ribavirin. Treatment interruption should be avoided; however, if treatment interruption is
necessary because of adverse reactions, neither SUNVEPRA nor DAKLINZA should be given
SUNVEPRA (asunaprevir)
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as monotherapy. If resumption of therapy is considered, the risks and benefits should be carefully
assessed (see WARNINGS AND PRECAUTIONS). For the SUNVEPRA/DAKLINZA
regimen, both drugs must be restarted at the same time.
Discontinuation of therapy is recommended for patients experiencing confirmed virologic
breakthrough (greater than 1 log10 IU/mL increase in HCV RNA from nadir).
Missed Dose
Patients should be instructed that if they miss a dose of SUNVEPRA the dose should be taken as
soon as possible if remembered within 8 hours of the scheduled dose time. However, if the
missed dose is remembered more than 8 hours after the scheduled dose, the dose should be
skipped and the next dose taken at the appropriate time. For instructions for missed doses of
DAKLINZA, peginterferon alfa, or ribavirin, refer to the respective Product Monograph.
OVERDOSAGE
For management of a suspected drug overdose, contact your regional Poison Control Centre.
There is limited clinical experience of overdose with SUNVEPRA. In phase 1 clinical trials,
healthy subjects who received up to 300 mg twice daily (gelatin capsule) for up to 10 days had
no unexpected adverse events. In clinical trials, asunaprevir use at the recommended dose or
higher is associated with elevated liver enzymes.
There is no known antidote for overdose of SUNVEPRA. Treatment of overdose with
SUNVEPRA should consist of general supportive measures, including monitoring of vital signs
and observation of the patient’s clinical status. Because asunaprevir is highly protein bound
(>99%) and has a molecular weight greater than 700, dialysis is unlikely to significantly reduce
plasma concentrations of the drug.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Asunaprevir is a direct acting antiviral agent (DAA) that inhibits the HCV NS3/4A serine
protease complex (see MICROBIOLOGY).
Pharmacodynamics
Cardiac Electrophysiology
The effect of asunaprevir on the QTc interval was evaluated in a randomized, double-blind,
positive- and placebo-controlled, parallel-group, nested-crossover study in 120 healthy subjects.
The effect of a supratherapeutic dose of asunaprevir (soft gelatin capsule) 300 mg twice daily
relative to placebo on QTc (using Fridericia’s correction) was evaluated on Days 3 and 10 of
active dosing. Moxifloxacin was the positive control. No statistically significant effects of
asunaprevir on placebo-corrected change in QTc (using Fridericia’s correction) or significant
SUNVEPRA (asunaprevir)
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relationship between plasma concentration and change in QTc were observed.
Pharmacokinetics
The pharmacokinetic properties of asunaprevir were evaluated in healthy adults and in subjects
with chronic HCV (see Table 9).
Table 9:
Summary of Twice-Daily Administration of SUNVEPRA in Healthy Adults
and HCV Infected Patients
PK Parameters
Healthy Subjects
HCV-Infected Patientsa
Geometric Mean (CV%)
Geometric Mean (CV%)
AUCTAU (ng●h/mL)
504 (58)
1887 (77)
Cmax (ng/mL)
128 (58)
572 (75)
Cmin (ng/mL)
9.5 (41)
47.6 (105)
a
Asunaprevir 100 mg twice daily in combination with daclatasvir (HALLMARK DUAL).
Absorption
The absolute oral bioavailability of asunaprevir soft capsule is 9.3%. Asunaprevir is rapidly
absorbed following administration with quantifiable concentrations within 30 minutes of
administration, and peak plasma concentrations occurring between 1 and 4 hours. In healthy
subjects, asunaprevir AUCTAU and Cmax increased 4-fold following a 2-fold increase in dose from
100 mg to 200 mg of the soft gel capsules, demonstrating greater than dose-proportional
increases in asunaprevir pharmacokinetics. Asunaprevir reaches steady state in 7-10 days of
twice-daily dosing. Exposure in HCV-infected patients was 4-fold greater than in healthy
subjects (see Table 9). Intersubject variability was high.
Effect of Food on Oral Absorption
In healthy subjects, administration of 100 mg asunaprevir soft capsule with a high-fat meal
(approximately 1000 kcal, approximately 50% from fat) increased the rate of absorption relative
to fasting conditions, but did not have a clinically meaningful effect on the overall bioavailability
of asunaprevir, with an increase in Cmax and AUC of 34% and 20%, respectively. Tmax of
asunaprevir when administered with food occurred about 1.5 hours post dose relative to about
2.5 hours post dose when administered under fasting conditions.
Distribution
Protein binding of asunaprevir in HCV-infected subjects was greater than 99% and was
independent of dose at the dose range studied (200-600 mg twice daily).
In vitro studies performed with HEK-293 cells indicated that asunaprevir is a substrate of the
liver uptake transporters OATP 1B1 and 2B1. In subjects who received asunaprevir 100 mg soft
capsule orally followed by a 100 µg 14C-asunaprevir intravenous dose, estimated volume of
distribution at steady state was 194 L, which is approximately 5 times total body water and
consistent with extensive distribution to tissues. Preferential liver distribution for asunaprevir
(liver concentrations up to 1240-fold relative to plasma in animals) is likely required for
asunaprevir to exert its antiviral effect.
SUNVEPRA (asunaprevir)
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Metabolism
Asunaprevir undergoes oxidative metabolism primarily mediated by CYP3A. Asunaprevir is also
a substrate of P-gp and OATP. The AUC of asunaprevir increased 9- to 15-fold when coadministered with ketoconazole (strong CYP3A4/P-gp inhibitor) or with rifampin (strong OATP
inhibitor) (see CONTRAINDICATIONS and DRUG INTERACTIONS). Asunaprevir appears
to weakly induce its own metabolism at the recommended dose of 100 mg twice daily. In a 14C
human absorption, distribution, metabolism, and excretion (ADME) study, asunaprevir
represented the majority of the radioactivity in plasma (~55% of AUC (0-24)), while metabolites
had AUC values below 5% of total plasma radioactivity for any given individual metabolite.
Excretion
Following single-dose oral administration of 14C-asunaprevir in healthy subjects, 84% of total
radioactivity was recovered in feces (primarily as metabolites) and less than 1% was recovered in
the urine (primarily as metabolites). Metabolism was the major route of asunaprevir elimination.
Of dose recovered in feces, unchanged asunaprevir accounted for 7.5% of the dose. Both
asunaprevir and its metabolites were detected in human bile. Following multiple-dose
administration of asunaprevir in healthy subjects, the terminal elimination half-life ranged from
17 to 23 hours. In subjects who received asunaprevir 100 mg soft capsule orally followed by a
100 µg 14C-asunaprevir intravenous dose, estimated total body clearance of asunaprevir was 49.5
L/h, indicating that asunaprevir is a moderate to high extraction ratio drug.
Special Populations and Conditions
Pediatrics
The pharmacokinetics of SUNVEPRA in pediatric patients has not been evaluated.
Geriatrics
Population pharmacokinetic analysis of data from clinical trials of SUNVEPRA indicated that
within the range evaluated (20-79) age had no clinically meaningful effect on the
pharmacokinetics of asunaprevir.
Gender
Population pharmacokinetic analysis of data from clinical trials of SUNVEPRA indicated that
gender had no clinically meaningful effect on the pharmacokinetics of asunaprevir.
Race
Population pharmacokinetic analysis of data from clinical trials of SUNVEPRA indicated that
race had no clinically meaningful effect on the pharmacokinetics of asunaprevir.
Hepatic Impairment
The pharmacokinetic properties of asunaprevir were studied in non–HCV-infected subjects with
mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment
and compared with unimpaired subjects. Subjects received asunaprevir (nonmarketed hard
capsule) 200 mg twice daily for 7 days. Mild hepatic impairment had minimal effect on
SUNVEPRA (asunaprevir)
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asunaprevir pharmacokinetics. Asunaprevir steady-state exposures (Cmax, AUCTAU, and Cmin)
were markedly higher in subjects with moderate (5.0-, 9.8-, and 32.9-fold, respectively) or severe
hepatic impairment (22.9-, 32.1-, and 76.5-fold, respectively) than in subjects without hepatic
impairment (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS;
Hepatic).
Renal Impairment
The pharmacokinetic properties of asunaprevir, as one of three components of an investigational
fixed dose combination tablet (asunaprevir/daclatasvir/an investigational non-nucleoside NS5B
inhibitor), were studied after multiple-dose administration in non-HCV infected subjects with
normal renal function (CrCL ≥90 mL/min, defined using the Cockcroft-Gault CrCL formula),
with mild (CrCl 60 to <90 mL/min), moderate (CrCl 30 to <60 mL/min), or severe (CrCl <30
mL/min) renal impairment not on hemodialysis, and with end-stage renal disease (ESRD) on
hemodialysis. Compared to subjects with normal renal function, the Cmax of asunaprevir was
estimated to be 29%, 65% and 88% higher and the AUC of asunaprevir was estimated to be
33%, 76% and 103% higher in subjects with mild, moderate and severe renal impairment,
respectively. Asunaprevir unbound Cmax was estimated to be 37%, 87% and 119% higher and
asunaprevir unbound AUC was estimated to be 41%, 99% and 137% higher for subjects with
mild, moderate and severe renal impairment, respectively, compared with subjects with normal
renal function. Subjects with ESRD requiring hemodialysis had an 11% decrease in asunaprevir
Cmax and a 16% decrease in AUC soon after hemodialysis compared to subjects with normal
renal function. Asunaprevir unbound Cmax and AUC decreased 2% and 6%, respectively, soon
after hemodialysis in subjects with ESRD requiring hemodialysis compared to subjects with
normal renal function (see WARNINGS AND PRECAUTIONS; Renal).
STORAGE AND STABILITY
Store at room temperature (15° to 30°C), protect from exposure to light and store in the original
container.
SPECIAL HANDLING INSTRUCTIONS
There are no special handling instructions.
DOSAGE FORMS, COMPOSITION AND PACKAGING
SUNVEPRA capsules are available for oral administration in 100 mg strengths of asunaprevir
containing the following non-medicinal ingredients: butylated hydroxytoluene (BHT), glycerol
monocaprylocaprate Type 1, medium-chain triglycerides, polysorbate 80. The capsule shell
contains gelatin, glycerine, sorbitol sorbitan solution and titanium dioxide.
SUNVEPRA 100 mg asunaprevir capsules are oval, opaque white to pale-yellow, soft gelatin
capsules filled with a clear solution. Capsules are imprinted with “BMS” in black on one line
and “711” in black on a second line below “BMS”.
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SUNVEPRA capsules, 100 mg are supplied in HDPE bottles containing 56 capsules
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PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name:
asunaprevir
Chemical name:
cyclopropanecarboxamide, N-[(1,1 dimethylethoxy)carbonyl]-3methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxy-1-isoquinolinyl)oxy]L-prolyl-1-amino-N-(cyclopropylsulfonyl)-2-ethenyl-,(1R,2S)
Molecular formula:
C35H46ClN5O9S
Molecular mass:
748.29
Structural formula:
Physicochemical properties:
Appearance: Asunaprevir drug substance is a white to off-white
powder.
Solubility: The aqueous solubility at 20°C and solution pH 5.72 is
0.0003 mg/mL. Asunaprevir is practically insoluble (< 100
µg/mL) across the physiological pH range (pH 1.2 to 6.8).
CLINICAL TRIALS
The efficacy and safety of SUNVEPRA in combination with DAKLINZA as an all-oral regimen
were evaluated in HCV genotype 1b infected patients with compensated liver disease in the
phase 3 open label HALLMARK DUAL trial. The efficacy and safety of SUNVEPRA in
combination with DAKLINZA, peginterferon alfa, and ribavirin were evaluated in patients with
HCV genotype 1 or 4 infection in the phase 3 HALLMARK QUAD trial (see Table 10 for
details of study designs).
Sustained virologic response (SVR, virologic cure) in both clinical trials was defined as HCV
RNA below the lower limit of quantification (LLOQ) at post-treatment week 12.
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Table 10:
Summary of Study Design for Trials of SUNVEPRA Combination Therapy
for Chronic Hepatitis C Infection
Treatment Regimens and
Dosage
Trial
Duration of
Treatment
Genotype/Population
HALLMARK
DUAL
(AI447028, openlabel)
SUNVEPRA (100 mg BID)
and DAKLINZA (60 mg QD)
n=645
HALLMARK
QUAD
(AI447029, openlabel)
SUNVEPRA (100 mg BID),
DAKLINZA (60 mg QD),
peginterferon alfa, and
Genotype (GT) 1b
24 weeks
Compensated liver disease
including cirrhosis
Placebo, n=102b
Treatment-naive, treatmentexperienced, interferon
intolerant/ineligible
GT 1, 4 treatment-experienced
24 weeks
Compensated liver disease
including cirrhosis
ribavirin a
a
Peginterferon alfa-2a: 180 μg given once weekly; ribavirin: <75 kg: 1000 mg/day (400 mg in morning and 600
mg in evening) with food; ≥75 kg: 600 mg twice daily with food.
b
This group received placebo for 12 weeks and were rolled over into another study and offered treatment with
SUNVEPRA in combination with DAKLINZA for 24 weeks.
SUNVEPRA in Combination with DAKLINZA for the Treatment of Patients with HCV
Genotype 1b (HALLMARK DUAL, AI447028)
The demographic and other baseline characteristics of the population in HALLMARK DUAL
are summarized in Table 11.
Table 11:
Demographic and Other Baseline Characteristics of HCV Genotype 1ba
Infected Patients (With or Without Compensated Cirrhosis) Treated with
SUNVEPRA and DAKLINZA in HALLMARK DUAL
Treatment-naive
Characteristic
Age (years)
Mean (range)
Gender
Male
Female
SUNVEPRA (asunaprevir)
b
Prior Nonresponders
c
Interferon
Intolerant/
d
DUAL
24 weeks
N=205
n (%)
Placebo
12 weeks
N=102
n (%)
(Partial, Null)
24 weeks
N=205
n (%)
53.1 (20 - 79)
52.5 (22 - 83)
56.1 (23 - 77)
58.0 (24 - 77)
101 (49.3%)
104 (50.7%)
54 (52.9%)
48 (47.1%)
111 (54.1%)
94 (45.9%)
98 (41.7%)
137 (58.3%)
Ineligible
24 weeks
N=235
n (%)
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Table 11:
Demographic and Other Baseline Characteristics of HCV Genotype 1ba
Infected Patients (With or Without Compensated Cirrhosis) Treated with
SUNVEPRA and DAKLINZA in HALLMARK DUAL
Treatment-naive
Characteristic
DUAL
24 weeks
N=205
n (%)
b
Placebo
12 weeks
N=102
n (%)
Prior Nonresponders
(Partial, Null)
24 weeks
N=205
n (%)
c
Interferon
Intolerant/
d
Ineligible
24 weeks
N=235
n (%)
Race
White
Black
Asian
Other
135 (65.9%)
14 (6.8%)
52 (25.4%)
4 (2.0%)
59 (57.8%)
8 (7.8%)
33 (32.4%)
2 (2.0%)
148 (72.2%)
10 (4.9%)
45 (22.0%)
2 (1.0%)
169 (71.9%)
10 (4.3%)
56 (23.8%)
0
Body Mass Index
(BMI)
≥ 30 kg/m2
30 (14.6%)
13 (12.7%)
32 (15.6%)
43 (18.3%)
NA
NA
84 (41.0%)
119 (58.0%)
NA
6.24
53 (25.9%)
152 (74.1%)
6.25
26 (25.5%)
76 (74.5%)
6.51
27 (13.2%)
178 (86.8%)
6.35
48 (20.4%)
187 (79.6%)
Cirrhosis (Child-Pugh
A)
Present
Absent
33 (16.1%)
172 (83.9%)
16 (15.7%)
86 (84.3%)
63 (30.7%)
142 (69.3%)
111 (47.2%)
124 (52.8%)
IL28B rs12979860
genotype
CC
CT
TT
76 (37.1%)
101 (49.3%)
28 (13.7%)
29 (14.1%)
123 (60.0%)
50 (24.4%)
82 (34.9%)
102 (43.4%)
41 (17.4%)
Prior Response
Partial
Null
e
HCV RNA
Mean log10 IU/mL
<800,000 IU/mL
≥800,000 IU/mL
a
Not done
VERSANT HCV genotype 2.0 assay (LIPA) was used for HCV genotype/subtype assessments.
b
Patients in the treatment-naive cohort were randomized 2:1 to receive SUNVEPRA and DAKLINZA for 24
weeks or placebo for 12 weeks (placebo patients were rolled over into another study and offered treatment with
SUNVEPRA and DAKLINZA for 24 weeks).
c
Null responders never attained ≥2 log10 decline in HCV RNA level after at least 12 weeks of peginterferon
alfa/ribavirin therapy or never attained ≥1 log10 decline in HCV RNA level after at least 4 weeks of peginterferon
alfa/ribavirin therapy. Partial responders received at least 12 weeks of prior peginterferon alfa/ribavirin therapy
and attained ≥2 log10 decline in HCV RNA level, but never achieved undetectable HCV RNA, or became HCV
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RNA undetectable and subsequently had a detectable HCV RNA result during peginterferon alfa ribavirin
treatment.
d
61% of patients were ineligible for interferon-based therapy, and 72% were intolerant of interferon-based therapy.
Interferon intolerant/ineligible patients met protocol-specified criteria for depression, anemia, neutropenia, and/or
thrombocytopenia with advanced fibrosis/cirrhosis.
e
HCV RNA values were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure
System. The assay had a LLOQ of 25 IU per mL.
Study Results
SVR, the primary endpoint, and outcomes for patients without SVR in HALLMARK DUAL are
shown by patient population in Table 12.
Table 12:
Treatment Outcomes: SUNVEPRA and DAKLINZA in Patients
Infected with HCV Genotype 1b in HALLMARK DUAL
Treatment Outcomes
Treatment Naive
N=203
n (%)
Prior Non-Responders
(Partial, Null )
24 weeks
N=205
n (%)
Interferon
Intolerant/Ineligible
24 weeks
N=235
n (%)
184 (91%)
169 (82%)
194 (83%)
168 (83%)
150 (73%)
159 (68%)
189 (93%)
174 (85%)
204 (87%)
19 (9%)
36 (18%)
41 (17%)
e
12 (6%)
29 (14%)
28 (12%)
e
9 (4%)
26 (13%)
20 (9%)
5/189 (3%)
7/174 (4%)
12/204 (6%)
2 (1%)
0
1 (<1%)
6 (3%)
9 (4%)
2 (1%)
26 (13%)
2 (1%)
25 (11%)
24 weeks
a
SVR12
RVR
b
c
d
EOTR
Outcomes for patients without SVR
Overall virologic failure
On-treatment virologic failure
Virologic breakthrough
Relapse
e
Missing post-treatment data
Discontinuation
Due to adverse event
Other
f
a
Two patients in the naive cohort who were treated but not randomized are excluded from the efficacy analysis.
b
SVR12: Sustained virologic response with HCV RNA <LLOQ at follow-up Week 12. Missing post-treatment
Week 12 HCV RNA was imputed using the using the Next Value Carried Backwards (NVCB) approach, ie, using
the next and closest available HCV RNA measurement after the follow-up Week 12 HCV RNA visit window.
c
RVR: HCV RNA undetectable at treatment Week 4.
d
EOTR: HCV RNA undetectable at End of Treatment.
e
On-treatment virologic failure includes subjects with virologic breakthrough (confirmed >1 log10 increase in
HCV RNA from nadir or any confirmed HCV RNA ≥LLOQ after <LLOQ during treatment), those with HCV
RNA ≥LLOQ at treatment week 8, and those with detectable HCV RNA at end of treatment. Relapse: HCV RNA
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undetectable at End of Treatment followed by confirmed HCV RNA ≥LLOQ during follow-up; rates are
calculated with a denominator of subjects with undetectable HCV RNA at the End of Treatment.
f
No deaths were observed in the HALLMARK DUAL study.
Among patients who had failed prior therapy, SVR rate was the same (82%) among the
84 patients with prior partial response and the 119 patients with prior null response. Response
was rapid (95% of patients had HCV RNA <LLOQ at week 4).
Subgroup analyses were performed for the primary efficacy endpoint (SVR12) for subgroups.
The response rates for selected subgroups are summarized in Table 13.
Table 13:
SVR in Selected Subgroups of Treatment Naive, Treatment Experienced and
Interferon Intolerant/Ineligible Patients with HCV Genotype 1b Infection in
HALLMARK DUAL
Treatment-Naive
24 weeks
N= 203
n/N (%)
Prior Non-Responders
(Partial, Null)
24 weeks
N=205
n/N (%)
Interferon
Intolerant/Ineligible
24 weeks
N= 235
n/N (%)
HCV RNA
<800,000 IU/mL
≥800,000 IU/mL
52/53 (98%)
132/150 (88%)
25/27 (93%)
144/178 (81%)
42/48 (88%)
152/187 (81%)
Cirrhosis
Present
Absent
29/32 (91%)
155/171 (91%)
55/63 (87%)
114/142 (80%)
90/111 (81%)
104/124 (84%)
162/169 (96%)
151/165 (92%)
172/191 (90%)
10/17 (59%)
7/25 (28%)
11/30 (37%)
Characteristic
Baseline NS5A
Without Y93H or
L31F/I/M/V
a
With Y93H or L31
F/I/M/Va
a
Analysis includes patients with available baseline NS5A sequence data. The overall prevalence of NS5A
polymorphisms at L31F/I/M/V or Y93H in HALLMARK DUAL was 12%: 4% of patients had L31
polymorphisms alone, 8% of patients had Y93H alone, and 0.3% of patients had L31I/M+Y93H together.
There were no differences in antiviral response due to race, body mass index (BMS) gender, age,
IL28B allele, or presence or absence of cirrhosis in any of the treatment populations. SVR rates
were consistently high across all categories of baseline viral load. Among patients 65 years of
age or older, 88% (117/133) achieved SVR, and among patients 75 years or older, 100% (10/10)
achieved SVR.
SUNVEPRA in Combination with DAKLINZA, Peginterferon Alfa, and Ribavirin for the
Treatment of Patients with HCV Genotype 1 or 4 (HALLMARK QUAD, AI447029)
The demographics and other baseline characteristics of the population in HALLMARK QUAD
are summarized in Table 14.
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Table 14:
Demographic and Other Baseline Characteristics of Previously Treated
Patientsa with HCV Genotype 1 or 4 Infection Treated with SUNVEPRA,
DAKLINZA, Peginterferon Alfa, and Ribavirin in HALLMARK QUAD
HCV Genotype 1
24 weeks
N=354
n (%)
HCV Genotype 4
24 weeks
N=44
n (%)
Age (years)
Mean (range)
52.9 (19-76)
50.8 (20-71)
Gender
Male
Female
240 (67.8%)
114 (32.3%)
33 (75.0%)
11 (25.0%)
Race
White
Black
Asian
Other
271 (76.6%)
33 (9.3%)
47 (13.3%)
3 (0.8%)
33 (75.0%)
4 (9.1%)
1 (2.3%)
6 (13.6%)
176 (49.7)
178 (50.3)
NA
NA
HCV RNA
Mean log10 IU/mL
<800,000 IU/mL
≥800,000 IU/mL
6.50
47 (13.3%)
307 (86.7%)
6.08
15 (34.1%)
29 (65.9%)
Cirrhosis (Child-Pugh A)
Present
Absent
73 (20.6%)
281 (79.4%)
20 (45.5%)
24 (54.5%)
IL28B rs12979860 genotype
CC
CT
TT
33 (9.3%)
231 (65.3%)
90 (25.4%)
3 (6.8%)
32 (70.5%)
10 (22.7%)
Characteristic
HCV Genotype
1a
1b
b
a
All patients were non-responders (null or partial) to prior treatment with peginterferon alfa-2a or -2b and
ribavirin. Null responders never attained ≥2 log10 decline in HCV RNA level after at least 12 weeks of
peginterferon alfa/ribavirin therapy or never attained ≥1 log10 decline in HCV RNA level after at least 4 weeks
of peginterferon alfa/ribavirin therapy. Partial responders received at least 12 weeks of prior peginterferon
alfa/ribavirin therapy and attained ≥2 log10 decline in HCV RNA level, but never achieved undetectable HCV
RNA, or became HCV RNA undetectable and subsequently had a detectable HCV RNA result during
peginterferon alfa ribavirin treatment.
b
HCV RNA values were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High
Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL.
Study Results
SVR, the primary endpoint, and outcomes for patients who did not achieve SVR in
HALLMARK QUAD are shown by patient population in Table 15. The demonstrated
effectiveness of SUNVEPRA, DAKLINZA, peginterferon alfa, and ribavirin treatment in HCV
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genotype 1 and 4 null responders indicates that this regimen is also expected to be effective in
HCV genotype 1 and 4 patients who are treatment naive.
Table 15:
Treatment Outcomes: SUNVEPRA in Combination with
DAKLINZA, Peginterferon Alfa, and Ribavirin in Previously
Treated Patients with HCV Genotype 1 or 4 Infection in
HALLMARK QUAD
Treatment Outcomes
SVR12
HCV Genotype 1
24 weeks
N=354
n (%)
HCV Genotype 4
24 weeks
N=44
n (%)
a
330 (93%)
44 (100%)
b
292 (83%)
36 (82%)
337 (95%)
43 (98%)
RVR
c
EOTR
Outcomes for patients without SVR
Overall virologic failure
24 (7%)
0
d
12 (3%)
0
d
11 (3%)
0
8/337 (2%)
0
4 (1%)
0
7 (2%)
12 (3%)
0
0
On-treatment virologic failure
Virologic breakthrough
Relapse
d
Missing post-treatment data
Discontinuation
Due to adverse event
Other
a
e
SVR12: Sustained virologic response with HCV RNA <LLOQ at follow-up Week 12. Missing post-treatment
Week 12 HCV RNA was imputed using the using the Next Value Carried Backwards (NVCB) approach, ie, using
the next and closest available HCV RNA measurement after the follow-up Week 12 HCV RNA visit window.
b
RVR: HCV RNA undetectable at treatment Week 4.
c
EOTR: HCV RNA undetectable at End of Treatment.
d
On-treatment virologic failure includes patients with virologic breakthrough (confirmed >1 log10 increase in
HCV RNA over nadir or any confirmed HCV RNA ≥LLOQ after confirmed undetectable), those with confirmed
HCV RNA ≥LLOQ at treatment week 8, and those with detectable HCV RNA at end of treatment. Relapse was
defined as HCV RNA ≥LLOQ during follow-up after HCV RNA undetectable at end of treatment.Relapse rates
are calculated with a denominator of subjects with undetectable HCV RNA at the end of treatment.
e
There were no deaths during the treatment phase of HALLMARK QUAD.
Response was rapid (98% of patients had HCV RNA <LLOQ at week 4).
Subgroup analyses were performed for the primary efficacy endpoint (SVR12) for selected
subgroups. The response rates for these subgroups are summarized in Table 16.
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Table 16:
SVR in Selected Subgroups of Treatment-Experienced Patients with HCV
Genotype 1 or 4 Infection in HALLMARK QUAD
HCV Genotype 1
24 weeks
N =354
n/N (%)
HCV Genotype 4
24 weeks
N =44
n/N (%)
Treatment History
Prior partial responder
Prior null responder
111/120 (93%)
219/234( 94%)
10/10 (100%)
34/34 (100%)
Genotype
1a
1b
154/176 (88%)
176/178 (99%)
NA
HCV RNA
<800,000 IU/mL
≥800,000 IU/mL
46/47 (98%)
284/307 (93%)
15/15 (100%)
29/29 (100%)
Cirrhosis
Present
Absent
66/73 (90%)
264/281 (94%)
20/20 (100%)
24/24 (100%)
Characteristic
There were no differences in antiviral response due to gender, age, BMI, baseline HCV RNA
level, presence or absence of baseline polymorphisms, IL28B allele status, or presence or
absence of cirrhosis in any of the treatment populations.
Long-Term Follow-Up
Limited data are available from an ongoing follow-up study to assess durability of response up to
3 years after treatment with SUNVEPRA. Among 255 patients who achieved SVR12 with
SUNVEPRA and DAKLINZA with a median duration of post-SVR12 follow-up of
approximately 8.5 months, 1 (<1%) relapse occurred. No relapses occurred among 31 patients
who achieved SVR12 with SUNVEPRA, DAKLINZA, peginterferon alfa, and ribavirin with a
median duration of post-SVR12 follow-up of approximately 18 months.
MICROBIOLOGY
Mechanism of Action
Asunaprevir is an inhibitor of the HCV NS3/4A serine protease complex. This NS3/4A enzyme
complex is responsible for processing the HCV polyprotein to yield mature viral proteins
required for viral replication.
Antiviral Activity
In biochemical assays, asunaprevir is most active against NS3/4A protease complexes
representing HCV genotype 1 (1a IC50 [50% inhibitory concentration] = 0.7 to 1.8 nM; 1b IC50
= 0.3 nM) and displays reduced activities against genotypes 2 (2a IC50 = 15 nM; 2b IC50 = 78
SUNVEPRA (asunaprevir)
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nM) and 3 (3a IC50 = 320 nM). Potencies against genotypes 4a, 5a, and 6a were 1.6, 1.7, and 0.9
nM, respectively. In cell-based HCV replicon assays, asunaprevir inhibited HCV genotype 1a,
1b, and 2a replication with effective concentration (50% reduction, EC50) values of 4, 1.2, and
230 nM, respectively. Against hybrid replicons encoding the NS3 protease domain representing
HCV genotype 4a, observed EC50 values ranged from 1.8 to 7.6 nM whereas reduced activities
against genotypes 2b and 3a NS3 hybrid replicons (2b EC50 = 480; 3a EC50 = 1162 nM) were
observed.
Asunaprevir showed additive and/or synergistic interactions with interferon alfa, daclatasvir,
HCV NS5B active-site or allosteric inhibitors targeting either Site I or II, and ribavirin in two- or
three-drug combination studies using a cell-based HCV replicon system. No antagonism of
antiviral activity was observed.
Resistance
See the DAKLINZA Product Monograph for the cell culture and clinical resistance profiles for
daclatasvir, including important information on NS5A resistance-associated polymorphisms.
In Cell Culture
HCV genotype 1a and genotype 1b replicons with reduced susceptibility to asunaprevir were
selected in cell culture and characterized for asunaprevir genotypic and phenotypic resistance.
Resistance to asunaprevir was evaluated by introducing emergent NS3 protease substitutions into
the respective replicon backbone. In HCV genotype 1a asunaprevir-resistant replicons,
predominant substitutions were detected at amino acids R155K, D168G, and I170T.
Recombinant replicons containing these substitutions confirmed their role in resistance to
asunaprevir (5- to 21-fold reduced susceptibility to asunaprevir).
In the HCV genotype 1b asunaprevir-resistant replicons, predominant substitutions were detected
at amino acid D168A/G/H/V/Y. Recombinant replicons containing these substitutions confirmed
their role in resistance to asunaprevir (16- to 280-fold reduced susceptibility to asunaprevir).
In Clinical Studies
Effect of Baseline HCV Polymorphisms on Treatment Response
Analyses were conducted to explore the association between naturally occurring baseline NS3
amino acid substitutions (polymorphisms) and treatment outcome.
SUNVEPRA in combination with DAKLINZA:
Baseline NS3 polymorphisms at amino acid positions associated with resistance were detected in
30.7% (278/905) of patients with available NS3 sequence. Nonstructural protein 3 resistance
associated polymorphisms (RAPs) in genotype 1b samples included V36I/L, T54A/S, V55A/I,
N77A/S, Q80K/L/R, S122 cysteine (C)/G/N/T, D168E, and F169L. The majority of detected
baseline NS3 RAPs conferred minimal change (≤ 2-fold) in asunaprevir susceptibility when
reference genotype 1b (Con1) replicons harboring the respective NS3 substitutions were
assessed. The baseline NS3 polymorphism D168E was the only tested polymorphism to confer a
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clinically meaningful loss in asunaprevir potency compared with the reference control
(asunaprevir EC50 for D168E = 67 nM vs Con1 control = 1 nM). The prevalence of this
polymorphism was 0.7% (6/905 patients), and it was present at baseline in 2% (3/138) of the
patients who failed treatment and had NS3 sequence. One of the 3 failures also had NS5AL31I/M-Y93H at baseline.
SUNVEPRA in combination with DAKLINZA, peginterferon alfa, and ribavirin:
Of 379 patients with available baseline NS3 sequence in HALLMARK QUAD (see CLINICAL
TRIALS), 4 patients had pre-existing signature asunaprevir-resistant polymorphisms at R155
(R155K/T) and/or D168 (D168E/N). Of the 4 patients, 3 patients had R155 substitutions and
experienced virologic failure (all 3 were infected with HCV genotype 1a).
Resistance Substitutions in Subjects not Achieving SVR
Treatment Emergent NS3 Amino Acid Substitutions in Pooled Data from Phase 2 and 3 Clinical
Trials: Patients who did not Achieve SVR with SUNVEPRA and DAKLINZA, or with
SUNVEPRA, DAKLINZA, Peginterferon Alfa, and Ribavirin are provided in Table 17.
Table 17:
Treatment Emergent NS3 Amino Acid Substitutions in Pooled Data
from Phase 2 and 3 Clinical Trials: Patients who did not Achieve SVR
with SUNVEPRA and DAKLINZA, or with SUNVEPRA,
DAKLINZA, Peginterferon Alfa, and Ribavirin
Treated Subjects
SUNVEPRA and
DAKLINZA
SUNVEPRA,
DAKLINZA, Peginterferon Alfa, and
Ribavirin
Genotype
1a
n=23a
Genotype
1b
n=2
Genotype 4
n=1a
% (n)
% (n)
118
16
1
0
97 (114)
94 (15)
100 (1)
0
0.8 (1)
25 (4)
0
0
R155Xc
3 (4)
50 (8)
0
0
R155K
D168Xd
0
94 (111)
50 (8)
44 (7)
0
100 (1)
0
0
D168V
D168E
40 (47)
21 (25)
0
38 (6)
100 (1)
0
0
0
Category
Genotype 1b
n=141
% (n)
Emerging amino acid
substitutions in NS3
Any substitution at NS3
position 36, 54, 56H/L, 77, 80,
122, 155, 168, and/or
170A/M/T
V36X + other noted NS3
substitutionsb
SUNVEPRA (asunaprevir)
% (n)
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Table 17:
Treatment Emergent NS3 Amino Acid Substitutions in Pooled Data
from Phase 2 and 3 Clinical Trials: Patients who did not Achieve SVR
with SUNVEPRA and DAKLINZA, or with SUNVEPRA,
DAKLINZA, Peginterferon Alfa, and Ribavirin
Treated Subjects
Category
SUNVEPRA and
DAKLINZA
Genotype
1a
n=23a
Genotype
1b
n=2
Genotype 4
n=1a
% (n)
% (n)
77 (91)
17 (20)
38 (6)
6 (1)
100 (1)
0
0
0
Less than 10%
Less than
10%
0
0
Genotype 1b
n=141
% (n)
Only D168X
D168X + other noted NS3
substitutionse
V36G, V36M, T54S, N77S,
Q80K/L/R, or S122G/I/N/T
a
SUNVEPRA,
DAKLINZA, Peginterferon Alfa, and
Ribavirin
% (n)
Of the 26 patients who did not achieve SVR12 by a modified intent-to-treat analysis (patients with missing values
for a given time point were considered as a failure for the specific time point only), 2 patients (1 with HCV
genotype 1a and 1 with HCV genotype 4) achieved SVR12 by an imputed analysis (for patients missing posttreatment week 12 HCV RNA, the next subsequent HCV RNA value was used).
b
X may include G (genotype 1b) or M (genotype 1a). Other noted NS3 substitutions include R155K or D168E.
c
X may include G, K, or Q.
d
X may include NS3 D168 substitutions A, E, F, H, N, T, V, or Y.
e
For genotype 1a patients, other NS3 substitutions included V36M; for genotype 1b patients, other NS3
substitutions included V36G, T54S, N77S, Q80R, S122D/G/I/T, or R155Q.
Persistence of Resistance-Associated Substitutions
Persistence of emergent NS3 resistance-associated substitutions was monitored post treatment in
patients who experienced treatment failure in phase 2/3 clinical trials of SUNVEPRA-containing
regimens. Among patients treated with SUNVEPRA and DAKLINZA, 41 patients were
monitored (32 patients for 24 weeks post treatment and 9 patients for 36-48 weeks post
treatment). Emergent HCV genotype 1b NS3 resistance-associated substitutions remained at
detectable levels in 19 of 32 patients monitored at 24 weeks post treatment and in 1 of 9 patients
monitored for 36-48 weeks post treatment.
The lack of detection of resistance-associated substitution does not necessarily indicate that drugresistant virus is no longer present. The long-term clinical impact of virus containing emergent
asunaprevir-resistant substitutions is unknown.
Cross Resistance
Cross-resistance between asunaprevir and other NS3/4A protease inhibitors is expected. Against
genotype 1a and 1b replicons harboring NS3 amino acid substitutions at V36 and T54
(telaprevir- and boceprevir-resistance variants), minimal effects on the anti-HCV activity of
SUNVEPRA (asunaprevir)
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asunaprevir have been observed. Conversely, against genotype 1a replicons harboring NS3
amino acid substitutions R155K, V36M + R155K, and genotype 1b replicons harboring
A156T/V (telaprevir-, boceprevir-, and simeprevir-resistance variants) and D168V (simeprevirresistance variant), reduced susceptibility to asunaprevir (6- to 357-fold loss) has been observed.
HCV replicons expressing asunaprevir-associated resistance substitutions remained fully
sensitive to interferon alfa and ribavirin, as well as other direct-acting antivirals with different
mechanisms of action, such as HCV NS5A and NS5B inhibitors.
NON-CLINICAL TOXICOLOGY
General Toxicity
Repeat-dose toxicity studies with asunaprevir were conducted in rats (≤ 6 months) and dogs
(≤ 9 months). The primary target organs for asunaprevir identified in the 1-month rat and dog
studies were the gastrointestinal (GI) tract and the liver. These findings occurred only at high
exposures and were not seen in the 6-month rat or 9-month dog studies. Following dosing for 1
month in rats at 600 mg/kg/day (81-fold the recommended human dose [RHD] AUC), increases
in serum alanine aminotransferase (ALT) activity and total bilirubin (TBIL) concentration
occurred without a histological correlate. In dogs at 300 mg/kg/day (375-fold RHD), asunaprevir
was not tolerated following 1 month of dosing, and findings at this dose included minimal to
slight hepatic coagulative necrosis with correlative increases in serum ALT and γglutamyltransferase activities and TBIL. Dogs given 300 mg/kg/day for 1 month exhibited
increased incidences of vomitus as the only finding suggestive of GI involvement.
Minimal hematologic changes were observed in both rats and dogs following dosing for 1 month
at 600 or 300 mg/kg/day, respectively, and included increased red cell distribution width and
decreased mean corpuscular volume. These changes reflected a shift to smaller red blood cell
size and suggested a change in iron metabolism. These hematologic changes were not adverse
due to their minimal nature and severity, and no histologic effect on bone marrow was observed
in the 1- or 6-month studies in rats and 1- or 9-month studies in dogs.
Other asunaprevir-related serum chemistry changes observed at 600 and 300 mg/kg/day (highest
doses tested) in rats and dogs in the 1-month studies included minimal to mild decreases in total
protein, albumin, and globulins. In rats, malabsorption and/or accelerated enteric loss of proteins
associated with intestinal alterations may have contributed to the observed changes in serum
proteins.
Relative to the 1-month findings, there was no progression of toxicity or new target organs in
chronic toxicity studies in rats or dogs. Asunaprevir was clinically well tolerated and no
toxicologically significant clinical or anatomic pathology changes were observed at the highest
doses of asunaprevir tested in rats (6 months; 136-fold RHD AUC) or dogs (9 months; 82-fold
RHD AUC).
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Juvenile Toxicology
In juvenile rats administered asunaprevir for 10 weeks, the toxicity profile was similar to that
observed in adult rats. Abdominal distension and body weight and food consumption changes
were considered adverse effects at 400 mg/kg/day (highest dose tested). The AUC for juvenile
rats at the no observed adverse effect level (NOAEL) was 98-fold the RHD AUC.
Carcinogenesis andMutagenesis
Asunaprevir was not carcinogenic in mice at AUC values 350-fold the RHD AUC or in rats at
54-fold the RHD AUC. No evidence of mutagenic or clastogenic activity was observed in in
vitro mutagenesis (Ames) tests, mammalian mutation assays in Chinese hamster ovary cells, or
in an in vivo oral micronucleus study in rats.
Impairment of Fertility
Asunaprevir had no effects on fertility in male or female rats (at AUC values that were 105- and
101-fold in males and females respectively, the RHD AUC).
Reproductive Toxicity
Asunaprevir was not a selective developmental toxicant when administered to pregnant mice or
rabbits during organogenesis at maternal doses associated with AUC values 472-fold (mouse)
and 1.2-fold (rabbit) the AUC at the recommended human dose (RHD). In a study of prenatal
and postnatal development in rats, developmental toxicity was not observed at doses up to
125 mg/kg/day, with AUC values 76-fold the RHD AUC. At the highest dose evaluated
(400 mg/kg/day), both maternal and developmental toxicity were observed. In rats, maternal
toxicity noted at 400 mg/kg/day in the dams included clinical signs (thinness, suspected
dehydration, and abdominal distention); decreased body weights late in gestation and early
lactation; reduced food consumption throughout gestation and lactation; and gross necropsy
observations of pale, enlarged adrenal glands in dams, with intestinal dilatation and thickening in
pups. Manifestations of developmental toxicity included reduced survival and reduced weight
that persisted into adulthood, with associated reductions in food consumption. The AUC value
associated with this dose is 193-fold the RHD AUC.
SUNVEPRA (asunaprevir)
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REFERENCES
1. Suzuki Y, Ikeda K, Suzuki F, et al. Dual oral therapy with daclatasvir and asunaprevir for
patients with HCV genotype 1b infection and limited treatment options. Journal of
Hepatology 2013; 58:655-62.
2. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis
C genotype 1. The New England Journal of Medicine. 2012; 366:216-24.
3. Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV
genotype 1b infection. Hepatology 2014; Jun;59(6):2083-91.
4. Chayama Kazuaki, Takahashi, Shoici, Toyota Joji et al. Dual Therapy with the Nonstructural
Protein 5A Inhibitor, Daclatasvir, and the Nonstructural Protein 3 Protease Inhibitor,
Asunaprevir, in Hepatitis C Virus Genotype 1b-Infected Null Responders. Hepatology 2012;
55;742-748.
SUNVEPRA (asunaprevir)
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READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE
PART III: PATIENT MEDICATION INFORMATION
PrSUNVEPRATM
(asunaprevir) Capsules
Read this carefully before you start taking SUNVEPRA and each time you get a refill. This
leaflet is a summary and will not tell you everything about this drug. Talk to your healthcare
professional about your medical condition and treatment and ask if there is any new information
about SUNVEPRA.
What is SUNVEPRA used for?
Pr
SUNVEPRA is used to treat chronic (long-lasting) infection with the hepatitis C virus (HCV),
genotypes 1 and 4, in adults. SUNVEPRA is used with other medicines that also treat chronic
HCV infection. These medicines are DAKLINZA alone or DAKLINZA with peginterferon alfa
and ribavirin.
People with hepatitis C infection have the virus in their blood and in their liver.
SUNVEPRA should not be taken alone.
SUNVEPRA has not been studied in children under 18 years of age.
How does SUNVEPRA work?
Pr
SUNVEPRA used with other medicines has been shown to cure chronic HCV infection in most
patients. Cure means the HCV is removed from your blood (remains at an undetectable level)
for 3 months after finishing all treatment.
SUNVEPRA blocks a protein from the virus that is needed to make new virus, and this helps to
lower the virus level in your body.
What are the ingredients in SUNVEPRA?
Medicinal ingredients: Asunaprevir
Non-medicinal ingredients: Butylated hydroxytoluene (BTE), glycerol monocaprylocaprate Type
1, medium-chain triglycerides and polysorbate 80. The capsule shell contains gelatin, glycerin,
sorbital sorbitan solution and titanium dioxide.
SUNVEPRA comes in the following dosage forms:
Pr
SUNVEPRA is available as capsules. Each capsule contains 100 mg of asunaprevir.
Asunaprevir is the medicinal ingredient. SUNVEPRA 100 mg capsules are oval, opaque white to
pale-yellow, soft-gelatin capsules with “BMS” in black on one line and “711” in black on a
second line below “BMS”.
SUNVEPRA (asunaprevir)
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Do not use SUNVEPRA if:
•
you are allergic to asunaprevir or any other ingredients in this product (see “What are
the ingredients in SUNVEPRA”)
•
you have certain liver problems other than hepatitis C, as determined by your healthcare
provider. Be sure to tell your healthcare provider of any liver problems you have or have
had.
•
you are taking certain medicines (see “Do not take SUNVEPRA if you take a medicine
that contains any of the following:” below).
•
your healthcare provider advises you to take ribavirin and peginterferon alfa with
SUNVEPRA and DAKLINZA, and you or your partner are pregnant or may become
pregnant. Ribavirin may cause birth defects or death of your unborn baby.
To help avoid side effects and ensure proper use, talk to your healthcare professional
before you take SUNVEPRA. Talk about any health conditions or problems you may have,
including if you:
•
have had a liver transplant, liver disease, or liver problems
•
have or have had hepatitis B. Hepatitis B activity may increase when medicines like
SUNVEPRA are used to treat hepatitis C infections. Your doctor will monitor your
hepatitis B levels and may do blood tests before, during and after hepatitis C treatment.
Your doctor may prescribe hepatitis B treatment
•
have HIV-1
•
have kidney disease
•
have any other medical condition
•
are pregnant or plan to become pregnant (see “Pregnancy”).
•
are breastfeeding or plan to breastfeed. It is not known if SUNVEPRA passes into your
breast milk. You and your healthcare provider should decide if you will take
SUNVEPRA or breastfeed. You should not do both.
•
are taking any medications
Pregnancy
If you are taking SUNVEPRA with DAKLINZA, peginterferon alfa and ribavirin: You or
your sexual partner should not become pregnant during treatment and for 6 months after
treatment ends.
-Females and males must use 2 effective forms of birth control during treatment and for
the 6 months after treatment with peginterferon alfa and ribavirin. Talk with your
healthcare provider about forms of birth control that may be used during this time. Some oral
birth control pills may not work with SUNVEPRA.
SUNVEPRA (asunaprevir)
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-Females must have a negative pregnancy test before starting treatment with peginterferon
alfa and ribavirin, every month while being treated, and every month for 6 months after your
treatment ends.
-If you or your female partner becomes pregnant while taking SUNVEPRA tell your
healthcare provider right away.
If you are NOT taking peginterferon alfa and ribavirin, the following information about
pregnancy applies:
-The effects of SUNVEPRA on pregnancy and the unborn child are not known. If you can
become pregnant, talk with your healthcare provider what forms of birth control to use. Some
oral birth control pills may not work with SUNVEPRA.
Liver Enzymes
Some people taking SUNVEPRA have abnormal results on tests that show how well the liver is
working. Your healthcare provider may request that you have blood tests every 2 weeks for the
first 12 weeks and then every 4 weeks while you take SUNVEPRA. If the test results are not at
normal levels, your healthcare provider may instruct you to stop taking SUNVEPRA.
Tell your healthcare professional about all the medicines you take, including any drugs,
vitamins, minerals, natural supplements or alternative medicines.
Pr
SUNVEPRA and other medicines may affect each other. This can cause you to have too much
or too little of SUNVEPRA or the other medicine in your body. The medicines may not work
well or you may have side effects. Do not start taking a new medicine without telling your
healthcare provider or pharmacist.
Do not take SUNVEPRA if you take a medicine that contains any of the following:
Antipsychotic agent: thioridazine♦
Anticonvulsants: phenytoin (Dilantin, Phenytek♦), carbamazepine (Carbatrol♦, Epitol♦,
Equetro♦, Tegretol), phenobarbital (Luminal♦), oxcarbazepine (Oxtellar XR♦, Trileptal)
Anti-infective agents:
rifampin (Rifadin, Rifamate♦, Rifater, Rimactane♦, rifabutin
(Mycobutin), rifapentine (Priftin♦), nafcillin♦, clarithromycin (Biaxin, Prevpac♦), erythromycin
(E.E.S., Eryc, Ery-Tab, Erythrocin, Erythrocin Stearate), telithromycin♦
Endothelin receptor antagonist: bosentan (Tracleer)
Glucocorticoid, systemic: dexamethasone (when administered by injection or taken by mouth)
Herbal products: St. John’s wort (Hypericum perforatum) or a product that contains St. John’s
wort
HIV non-nucleoside reverse transcriptase inhibitors: efavirenz (Sustiva, Atripla), etravirine
(Intelence), nevirapine (Viramune)
SUNVEPRA (asunaprevir)
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HIV protease inhibitors: atazanavir (Reyataz), darunavir/ritonavir, indinavir (Crixivan),
lopinavir/ritonavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Invirase),
fosamprenavir (Telzir)
Pharmacokinetic enhancer: Cobicistat or cobicistat-containing regimen
Wakefulness promoting agent: modafinil (Provigil)
Antifungal agents: ketoconazole (when taken by mouth) (Nizoral), itraconazole (when taken by
mouth) (Sporanox, Onmel♦), voriconazole (when taken by mouth or administered by injection)
(Vfend), fluconazole (when taken by mouth or administered by injection) (Diflucan),
posaconazole (Posanol)
Calcium channel blocker: diltiazem (Cardizem, Dilacor XR, Tiazac), verapamil (Covera-HS♦,
Calan♦, Verelan)
Immunosuppressants: cyclosporine (Neoral, Sandimmune)
Lipid-lowering agent: gemfibrozil
Other drugs that may interact with SUNVEPRA and may require dosage adjustment of the
other drug include:
•
dabigatran (Pradaxa) (used to prevent blood clots),
•
dextromethorphan (a cough suppressant that is an ingredient in many over-the counter
cold medicines, for example, Dimetapp, Robitussin, Theraflu, etc.)
•
digoxin (Digifab, Digox, Lanoxin), flecainide (Tambocor), propafenone (Rhythmol)
(medicines to treat irregular heartbeats)
•
hormonal contraceptives
•
midazolam (medicine used as a sedative or to prevent convulsions)
•
rosuvastatin (Crestor), atorvastatin (Caduet, Lipitor, Liptruzet♦), fluvastatin (Lescol),
simvastatin (Zocor), pitavastatin♦, pravastatin (Pravachol) (medicines that lower
cholesterol)
•
amitriptyline♦, imipramine, nortriptyline (Aventyl) (medicines to treat depression)
♦ Not marketed in Canada
This is not a complete list of medicines that could interact with SUNVEPRA. Know the
medicines you take. Keep a list of them with you to show to your healthcare provider and
pharmacist when you get a new medicine.
How to take SUNVEPRA:
Do not take PrSUNVEPRA alone to treat chronic hepatitis C infection. SUNVEPRA should be
used together with DAKLINZA or with DAKLINZA, peginterferon alfa, and ribavirin.
SUNVEPRA (asunaprevir)
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Take SUNVEPRA exactly as your healthcare provider tells you to take it. Do not take more or
fewer capsules than what your healthcare provider tells you to take.
Do not stop taking SUNVEPRA without first talking with your healthcare provider.
Usual adult dose:
Take 1 capsule of SUNVEPRA (100 mg) 2 times each day with or without food.
Overdose:
If you think you have taken too much SUNVEPRA, contact your healthcare professional,
hospital emergency department or regional Poison Control Centre immediately, even if there
are no symptoms.
Missed Dose:
It is important not to miss a dose of PrSUNVEPRA. If you do miss a dose and it is:
•
less than 8 hours from the time you usually take SUNVEPRA, take the missed dose as
soon as possible. Take the next dose at the usual time.
•
more than 8 hours from the time you usually take SUNVEPRA, skip the missed dose.
Take the next dose at the usual time.
Do not take two doses of SUNVEPRA at the same time to make up for the missed dose.
What are possible side effects from using SUNVEPRA?
These are not all the possible side effects you may feel when taking PrSUNVEPRA. If you have
any side effects not listed here, contact your healthcare professional. Please also see “Do not use
SUNVEPRA if”.
Liver problems. Some people taking SUNVEPRA have abnormal results on tests that show how
well the liver is working.
The most common side effects when SUNVEPRA is taken in combination with DAKLINZA
include:
•
headache
•
tiredness
The most common side effects when SUNVEPRA is taken in combination with DAKLINZA,
peginterferon alfa, and ribavirin include:
•
tiredness
•
headache
•
itching
•
unusual weakness
•
flu-like symptoms
SUNVEPRA (asunaprevir)
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Page 46 of 48
•
difficulty sleeping (insomnia)
•
low red blood cell count
•
rash
•
hair loss
•
irritability
•
nausea
When SUNVEPRA is used with peginterferon alfa and ribavirin, the following effects have
occurred:
Serious side effects and what to do about them
Talk to your healthcare professional
Symptom / effect*
Only if severe
In all cases
VERY COMMON
Effect: Low red blood cell
counts (anemia)
Symptoms:
-Tiredness
-Headache
-Shortness of breath
-Dizziness
-Looking pale

Stop taking drug
and get immediate
medical help
√
Effect: Low white blood cell
counts (neutropenia)
√

Symptoms:
-Increased infections
COMMON
Effect: Low blood platelet
(thrombocytopenia)
√

Symptoms:
-Bruising and increased
tendency to bleed
*These side effects are commonly associated with peginterferon alfa and ribavirin therapy.
This is not a complete list of side effects. If you have a troublesome symptom or side effect that
is not listed here or becomes bad enough to interfere with your daily activities, talk to your
healthcare professional.
SUNVEPRA (asunaprevir)
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Reporting Side Effects
You can help improve the safe use of health products for Canadians by reporting serious and
unexpected side effects to Health Canada. Your report may help to identify new side effects
and change the product safety information.
3 ways to report:
•
Online at MedEffect;
•
By calling 1-866-234-2345 (toll-free);
•
By completing a Consumer Side Effect Reporting Form and sending it by:
- Fax to 1-866-678-6789 (toll-free), or
- Mail to: Canada Vigilance Program
Health Canada, Postal Locator 1908C
Ottawa, ON
K1A 0K9
Postage paid labels and the Consumer Side Effect Reporting Form are available
at MedEffect.
NOTE: Contact your health professional if you need information about how to manage your
side effects. The Canada Vigilance Program does not provide medical advice.
Storage:
Store PrSUNVEPRA at room temperature (15° to 30°C) and protect from light.
Store SUNVEPRA in the original container.
Keep SUNVEPRA and all medicines out of the reach and sight of children.
If you want more information about SUNVEPRA:
•
Talk to your healthcare professional
•
Find the full product monograph that is prepared for healthcare professionals and
includes this Patient Medication Information by visiting the Health Canada website; the
manufacturer’s website http://www.bmscanada.ca, or by calling 1-866-463-6267.
This leaflet was prepared by Bristol-Myers Squibb Canada.
Last Revised January 26, 2017
TM
of Bristol-Myers Squibb Holdings Ireland used under license by Bristol-Myers Squibb
Canada.
Other brands listed are trademarks of their respective owners.
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